IL-2-Dependent Regulation of Immune Homeostasis and Response to Infection

Abstract

Interleukin-2 (IL-2) is a critical regulator of immune homeostasis through its impact on both regulatory T (Treg) and effector T (Teff) cells. However, the precise role of IL-2 in the homeostatic maintenance and function of Treg cells in the adult peripheral immune system remains unclear. Here, we report that neutralization of IL-2 in mice abrogated all IL-2 receptor signaling in Treg cells but was well tolerated and only gradually impacted Treg cell function and immune homeostasis. Additionally, despite substantially reduced IL-2 sensitivity, Treg cells maintained selective IL-2 signaling and prevented immune dysregulation following treatment with the inhibitory anti-CD25 antibody PC61. Reduction of Treg cells with a depleting version of the same CD25 antibody permitted CD8+ Teff proliferation before progressing to more widespread immune dysregulation. Thus, despite severely curtailed CD25 expression and function, Treg cells retain selective access to IL-2 that supports their anti-inflammatory functions in vivo. Antibody-mediated targeting of CD25 is being actively pursued for treatment of autoimmune disease and preventing allograft rejection, and our findings help inform therapeutic manipulation and design for optimal patient outcomes. Treg cells play an essential role in return to homeostasis and maintenance of immunologic tolerance after response to infection, and the role of IL-2 in this context is unknown. In contrast to the minimal impact of short term IL-2 neutralization at homeostasis, antibody blockade of IL-2 during acute VSV infection results in reduced frequencies of Treg cells and increased frequencies of CD4+ Teff cells at day 7 post infection. However, Teff cell responses to viral peptide stimulation were similar regardless of the level of IL-2 signaling. Mice harboring CD4+ T cells that produce impaired levels of IL-2 displayed a similarly dysregulated balance of Treg and Teff cells after VSV infection. Our data suggest that viral infection under suboptimal IL-2 conditions may allow expansion of bystander CD4+ T cells that could be a trigger of an autoinflammatory or autoimmune state.